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Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.

Gastric cancer (GC) is a highly aggressive malignancy with limited treatment options for advanced‐stage patients. Recent studies have highlighted the role of circular RNA (circRNA) as a novel regulator of cancer progression in various malignancies. However, the underlying mechanisms by which circRNA contributes to the development and progression of GC remain poorly understood. In this study, we utilized microarrays and real‐time quantitative polymerase chain reaction (qRT‐PCR) to identify and validate a downregulated circRNA, hsa_circ_0003251 (referred to as circWNK1), in paired GC and normal tissues. Through a series of in vitro and in vivo gain‐of‐function and loss‐of‐function assays, we demonstrated that circWNK1 exerts inhibitory effects on the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of GC cells. Additionally, we discovered that circWNK1 acts as a competitive endogenous RNA (ceRNA) for SMAD7 by sequestering miR‐21‐3p. Our findings were supported by comprehensive biological information analysis, as well as RNA pull‐down, luciferase reporter gene, and western blot assays. Notably, the downregulation of circWNK1 in GC cells resulted in reduced SMAD7 expression, subsequently activating the TGF‐β signaling pathway. Collectively, our study reveals that circWNK1 functions as a tumor suppressor in GC by regulating the miR‐21‐3p/SMAD7‐mediated TGF‐β signaling pathway. Furthermore, circWNK1 holds promise as a potential biomarker for the diagnosis and treatment of GC. In this study, we investigated the role of circWNK1, a specific circular RNA, in the development of gastric cancer (GC). Our findings revealed that circWNK1 expression is downregulated in GC and is associated with a poorer prognosis. Overexpressing circWNK1 inhibited GC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Mechanistically, circWNK1 acted as a competitive endogenous RNA (ceRNA) for SMAD7 by sequestering miR‐21‐3p, thereby activating the TGF‐β signaling pathway. These results suggest that circWNK1 may serve as a potential biomarker and therapeutic target for GC.

Cell division cycle associated 7 (CDCA7) is a copy number amplification gene that contributes to the metastasis and invasion of tumors, including esophageal squamous cell carcinoma (ESCC). This present study aimed at clarifying whether high expression of CDCA7 promotes the metastasis and invasion of ESCC cell lines and exploring the underlying mechanisms implicated in epithelial–mesenchymal transition (EMT) of ESCC. The role of CDCA7 in the regulation of ESCC metastasis and invasion was evaluated using ESCC cell lines. Expression of EMT‐related markers including E‐cadherin, N‐cadherin, Vimentin, Snail, and Slug, transforming growth factor β (TGF‐β) signaling pathway including Smad2/3, p‐Smad2/3, Smad4, and Smad7 were detected in CDCA7 knockdown and overexpressed cell lines. Dual‐luciferase reporter assay and rescue assay were used to explore the underlying mechanisms that CDCA7 contributed to the metastasis and invasion of ESCC. High CDCA7 expression significantly promoted the metastasis and invasion of ESCC cell lines both in vivo and in vitro. Additionally, the expression of CDCA7 positively correlated with the expression of N‐cadherin, Vimentin, Snail, Slug, TGF‐β signaling pathway and negatively correlated with the expression of E‐cadherin. Furthermore, CDCA7 transcriptionally regulated the expression of Smad4 and Smad7. Knockdown of CDCA7 inhibited the TGF‐β signaling pathway and therefore inhibited EMT. Our data indicated that CDCA7 was heavily involved in EMT by regulating the expression of Smad4 and Smad7 in TGF‐β signaling pathway. CDCA7 might be a new therapeutic target in the suppression of metastasis and invasion of ESCC. High cell division cycle associated 7 (CDCA7) expression significantly promoted the metastasis and invasion of esophageal squamous cell carcinoma cell lines both in vivo and in vitro. The expression of CDCA7 positively correlated with the expression of N‐cadherin, Vimentin, Snail, Slug, transforming growth factor β signaling pathway and negatively correlated with the expression of E‐cadherin. CDCA7 transcriptionally regulated the expression of Smad4 and Smad7

Transforming growth factor beta (TGF‐β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation‐associated responses. However, the antiviral activities and mechanisms of TGF‐β isoforms, including TGF‐β1, TGF‐β2 and TGF‐β3, remain unclear. Here, we demonstrated that all of the three TGF‐β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF‐β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF‐β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF‐β/SMAD signalling pathway–dependent and TGF‐β/SMAD signalling pathway–independent manners. TGF‐β isoforms showed additional anti‐HCV activities when combined with each other. However, the elevated TGF‐β1 and TGF‐β2, not TGF‐β3, could also induce liver fibrosis with a high expression of type I collagen alpha‐1 and α‐smooth muscle actin in LX‐2 cells. Our results showed a new insight into TGF‐β isoforms in the HCV‐related liver disease progression.

Cervical cancer (CC) is a prevalent female malignancy strongly influenced by the tumor microenvironment (TME). This study focuses on the role of TGF-β signaling in cancer-associated fibroblasts (CAFs) and its interaction with immune cells, aiming to elucidate its impact on CC progression. The TME of CC patients was analyzed using scRNA-seq data and we identified the major cell types in the TME with a focus on the activation of the TGF-β signaling pathway in fibroblasts. Gene modules related to the TGF-β signaling pathway were identified by Weighted correlation network analysis (WGCNA). Using The Cancer Genome Atlas Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) dataset, a prognostic gene model was constructed by univariate Cox, LASSO Cox and multivariate Cox regression analyses. For cellular validation, the mRNA level of prognostic model-related genes was tested via quantitative real-time real-time polymerase chain reaction (PCR). Thereafter, the following assays, including cell counting kit-8, scratch and wound healing assays, were applied to assess the viability, migration and invasion of CC cells. Analysis at single-cell resolution identified nine major cell types in the TME, and significant activation of the TGF-β signaling pathway in fibroblasts was correlated with tumor proliferation and differentiation. Strong TGF-β signaling communication between fibroblasts and macrophages and NK/T cells suggested a crucial role in the shaping of the immunosuppressive microenvironment. WGCNA analysis identified gene modules significantly associated with the TGF-β signaling pathway. The prognostic model constructed based on three genes, , and , demonstrated good predictive ability in multiple datasets, validating its potential for clinical application. Meanwhile, the cellular validation assays have revealed the higher expression of and and lower expression of SHF in CC cells. Further, knockdown suppressed the viability, migration and invasion of CC cells. This study confirmed the important role of the TGF-β signaling pathway in CC, especially in fibroblasts on tumor microenvironment and tumor progression. The current model could effectively evaluate the prognosis of CC, providing a theoretical foundation for developing CC therapies according to the TGF-β signaling pathway. The present results provide new perspectives for further research on the pathological mechanisms and clinical management of CC.

Objectives This study investigated the synergistic effects of gingival stem cell conditioned media (GSC‐CM) and low‐level laser therapy (LLLT) on stimulating PDLSCs, explicitly focusing on the molecular basis of enhancing the Wnt and TGF‐β signaling pathways. Material and Methods PDLSCs were isolated and GSC‐CM were prepared and characterized. Five groups were utilized: control, osteogenic induction medium (positive control), GSC‐CM, LLLT (980 nm, 1.5 J/cm²), and a combination of GSC‐CM with LLLT. Cell viability was assessed using the MTT assay on Days 1, 2, and 3. Osteogenic differentiation of PDLSCs was assessed using mineralization assays employing Alizarin Red staining, and molecular analyses of osteogenic markers (RUNX2, ALP, OCN) and signaling‐related genes (CTNNβ1, TGFβ1) conducted via RT‒PCR. Results The findings revealed that the dual application of GSC‐CM and LLLT significantly enhanced cell viability and osteogenic differentiation of PDLSCc compared to the effects of the individual treatment modalities. Moreover, the study revealed elevated expression levels of osteogenic markers across all the experimental groups, specially the combination group, which showed the highest levels. Significantly, the combination treatment group displayed superior outcomes in this regard. The results also suggest potential activation of Wnt/β‐catenin and TGF‐β signaling components. Conclusions This study highlights the significant effects of using GSC‐CM and LLLT to improve PDLSC survival and osteogenic differentiation.

Background Increasing evidence shows that tRNA‐derived small RNAs (tsRNAs) are not only by‐products of transfer RNAs, but they participate in numerous cellular metabolic processes. However, the role of tsRNAs in skeletal muscle regeneration remains unknown. Methods Small RNA sequencing revealed the relationship between tsRNAs and skeletal muscle injury. The dynamic expression level of 5'tiRNA‐Gly after muscle injury was confirmed by real‐time quantitative PCR (q‐PCR). In addition, q‐PCR, flow cytometry, the 5‐ethynyl‐2'‐deoxyuridine (Edu), cell counting kit‐8, western blotting and immunofluorescence were used to explore the biological function of 5'tiRNA‐Gly. Bioinformatics analysis and dual‐luciferase reporter assay were used to further explore the mechanism of action under the biological function of 5'tiRNA‐Gly. Results Transcriptome analysis revealed that tsRNAs were significantly enriched during inflammatory response immediately after muscle injury. Interestingly, we found that 5'tiRNA‐Gly was significantly up‐regulated after muscle injury (P < 0.0001) and had a strong positive correlation with inflammation in vivo. In vitro experiments showed that 5'tiRNA‐Gly promoted the mRNA expression of proinflammatory cytokines (IL‐1β, P = 0.0468; IL‐6, P = 0.0369) and the macrophages of M1 markers (TNF‐α, P = 0.0102; CD80, P = 0.0056; MCP‐1, P = 0.0002). On the contrary, 5'tiRNA‐Gly inhibited the mRNA expression of anti‐inflammatory cytokines (IL‐4, P = 0.0009; IL‐10, P = 0.0007; IL‐13, P = 0.0008) and the mRNA expression of M2 markers (TGF‐β1, P = 0.0016; ARG1, P = 0.0083). Flow cytometry showed that 5'tiRNA‐Gly promoted the percentage of CD86+ macrophages (16%, P = 0.011) but inhibited that of CD206+ macrophages (10.5%, P = 0.012). Immunofluorescence showed that knockdown of 5'tiRNA‐Gly increased the infiltration of M2 macrophages to the skeletal muscles (13.9%, P = 0.0023) and inhibited the expression of Pax7 (P = 0.0089) in vivo. 5'tiRNA‐Gly promoted myoblast the expression of myogenic differentiation marker genes (MyoD, P = 0.0002; MyoG, P = 0.0037) and myotube formation (21.3%, P = 0.0016) but inhibited the positive rate of Edu (27.7%, P = 0.0001), cell viability (22.6%, P = 0.003) and the number of myoblasts in the G2 phase (26.3%, P = 0.0016) in vitro. Mechanistically, we found that the Tgfbr1 gene is a direct target of 5'tiRNA‐Gly mediated by AGO1 and AGO3. 5'tiRNA‐Gly dysregulated the expression of downstream genes related to inflammatory response, activation of satellite cells and differentiation of myoblasts through the TGF‐β signalling pathway by targeting Tgfbr1. Conclusions These results reveal that 5'tiRNA‐Gly potentially regulated skeletal muscle regeneration by inducing inflammation via the TGF‐β signalling pathway. The findings of this study uncover a new potential target for skeletal muscle regeneration treatment.

The progression from acute kidney injury (AKI) to chronic kidney disease (CKD) has become a focal point of investigation, with the TGF-β/Smad signaling pathway emerging as a key mediator in this process. The present review assesses how TGF-β/Smad contributes to renal fibrosis and the subsequent deterioration of kidney function following AKI. Drawing on recent experimental and clinical findings, this study explores how pathway activation promotes tubular cell injury, inflammation and interstitial fibrosis. By examining these molecular and cellular events, this study offers fresh insights into the complex mechanisms that underlie the AKI-CKD transition and highlights potential therapeutic strategies aimed at interrupting or slowing disease progression.

Background Lower back pain is often accredited to loss of intervertebral disc (IVD) height and compromised spine stability as a result of intervertebral disc degeneration (IVDD). We aim to locally use bleomycin to induce the fibrotic transformation of bone marrow stromal cells (BMSCs) as a means to induce reparative fibrosis to slow down the height loss. Methods IVDs from patients were gathered for histological examination. The expression of the transforming growth factor beta 1 (TGF-β) signaling pathway was determined by qPCR and western blotting. Nucleus pulposus (NP) cells, annulus fibrosus (AF) cells, and the rats’ bone marrow stromal cells (BMSC) were cultured and their responsiveness to bleomycin was evaluated by Cell Counting Kit-8, comet assay, transwell migration, and wound healing assays. Rat IVDD models were created by puncture and rescued by bleomycin injection, and the effectiveness was evaluated by images (X-ray and MRI) and atomic force microscope. Results Histological examination showed increased levels of pro-fibrotic markers in IVDD tissues from patients. AF cells and BMSC cells were induced to adopt a pro-fibrotic phenotype with increased expression fibrotic markers Col1a1, Col3a1, and FSP1. The pro-fibrotic effect of bleomycin on AF cells and BMSCs was in part due to the activation of the TGFβ-TGFβR1-SMAD2/3 signaling pathway. Pharmacological inhibition or gene knock-down of TGFβR1 could mitigate the pro-fibrotic effects. Conclusion Locally, injection of bleomycin in rats’ IVD induced rapid fibrosis and maintained its height through the TGFβ-TGFβR1-SMAD2/3 signaling pathway.

Background Hypertrophy ligamentum flavum is a prevalent chronic spinal condition that affects middle‐aged and older adults. However, the molecular pathways behind this disease are not well comprehended. Objective The objective of this work is to implement bioinformatics techniques in order to identify crucial biological markers and immune infiltration that are linked to hypertrophy ligamentum flavum. Further, the study aims to experimentally confirm the molecular mechanisms that underlie the hypertrophy ligamentum flavum. Methods The corresponding gene expression profiles (GSE113212) were selected from a comprehensive gene expression database. The gene dataset for hypertrophy ligamentum flavum was acquired from GeneCards. A network of interactions between proteins was created, and an analysis of functional enrichment was conducted using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. An study of hub genes was performed to evaluate the infiltration of immune cells in patient samples compared to tissues from the control group. Finally, samples of the ligamentum flavum were taken with the purpose of validating the expression of important genes in a clinical setting. Results Overall, 27 hub genes that were differently expressed were found through molecular biology. The hub genes were found to be enriched in immune response, chemokine‐mediated signaling pathways, inflammation, ossification, and fibrosis processes, as demonstrated by GO and KEGG studies. The main signaling pathways involved include the TNF signaling pathway, cytokine–cytokine receptor interaction, and TGF‐β signaling pathway. An examination of immunocell infiltration showed notable disparities in B cells (naïve and memory) and activated T cells (CD4 memory) between patients with hypertrophic ligamentum flavum and the control group of healthy individuals. The in vitro validation revealed markedly elevated levels of ossification and fibrosis‐related components in the hypertrophy ligamentum flavum group, as compared to the normal group. Conclusion The TGF‐β signaling pathway, TNF signaling pathway, and related hub genes play crucial roles in the progression of ligamentum flavum hypertrophic. Our study may guide future research on fibrosis of the ligamentum flavum. This study revealed significant amounts of TGF‐β1 expression and associated signaling pathways in HLF. Our study indicates that the activation of the TNF signaling system by TNF‐a results in the ossification of the LF. Additionally, the TGF‐β1 signaling route promotes LF fibrosis, which in turn leads to HLF. Meanwhile, HLF may be initiated by an upregulation of collagen synthesis in fibroblasts as a result of macrophage infiltration. These findings offer fresh perspectives in comprehending the pathophysiology of HLF.